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First-in-Human Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy

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ClinicalTrials.gov Identifier: NCT04360434
Recruitment Status : Recruiting
First Posted : April 24, 2020
Last Update Posted : June 14, 2022
Sponsor:
Information provided by (Responsible Party):
Neurimmune AG

Brief Summary:
A phase 1, randomized, placebo-controlled, double-blind, dose escalation trial combining single-ascending dose and multiple-ascending dose phases of NI006 or placebo, followed by an open-label extension phase in subjects with Amyloid Transthyretin Cardiomyopathy (ATTR-CM).

Condition or disease Intervention/treatment Phase
Amyloid Transthyretin Cardiomyopathy Drug: NI006 Drug: Placebo Phase 1

Detailed Description:

This phase 1, randomized, placebo-controlled, double-blind trial in subjects with Amyloid Transthyretin Cardiomyopathy (ATTR-CM) consists of single-ascending dose (SAD) and multiple-ascending dose (MAD) phases, followed by an open-label extension (OLE) phase.

In the SAD phase subjects are randomized in a 4:2 ratio to receive a single infusion of NI006 or placebo.

Subjects completing the SAD phase will be enrolled in the MAD phase upon evaluation of all available safety data and receive a maximum of 3 additional infusions of NI006 or placebo every 28 days.

Subjects completing the MAD phase will have the possibility to continue in an OLE phase with treatment up-titrations and switch from placebo to NI006 and receive up to 8 infusions of NI006 every 28 days.

Subjects of cohort 1 to 5 who received at least one dose of NI006 during the OLE phase will have the possibility for a second OLE phase (OLE2) after completing the OLE phase and receive up to 10 additional infusions of NI006 every 28 days.

In total, about 42 subjects are planned to be enrolled in 7 cohorts of 6 subjects each, at 6 ascending dose levels.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1, First-in-Human, Double-Blind, Placebo-Controlled, Multicenter, Single and Multiple Ascending Dose Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy Followed by an Open-Label Extension
Actual Study Start Date : February 10, 2020
Estimated Primary Completion Date : February 28, 2023
Estimated Study Completion Date : February 28, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: NI006
Dose escalation in up to 6 dose cohorts. Subjects will be administered a single dose of NI006 in the SAD, multiple doses of NI006 in the MAD and OLE phases.
Drug: NI006
NI006 will be administered intravenously

Placebo Comparator: Placebo

Subjects will be administered a single dose of placebo in the SAD phase and multiple doses of placebo in the MAD phase.

In the OLE phase, all subjects will be administered multiple doses of NI006.

Drug: Placebo
Formulation buffer of NI006, matching volume of NI006 doses will be administered intravenously




Primary Outcome Measures :
  1. Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram [ Time Frame: 4 months ]
    Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram

  2. Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram [ Time Frame: 12 months ]
    Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram

  3. Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram [ Time Frame: additional up to 10 months ]
    Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram


Secondary Outcome Measures :
  1. NI006 pharmacokinetic profile and parameters - Cmax [ Time Frame: 4 months ]
    Maximum observed serum concentration (Cmax) of NI006

  2. NI006 pharmacokinetic profile and parameters - Tmax [ Time Frame: 4 months ]
    Time to maximum observed serum concentration (Tmax) of NI006

  3. NI006 pharmacokinetic profile and parameters - AUCinf [ Time Frame: 1 month ]
    Area under the serum concentration-time curve from zero to infinity (AUCinf) of NI006

  4. NI006 pharmacokinetic profile and parameters - CL [ Time Frame: 4 months ]
    Serum clearance (CL) of NI006

  5. NI006 pharmacokinetic profile and parameters - Vz [ Time Frame: 4 months ]
    NI006 apparent volume of distribution during terminal phase (Vz)

  6. NI006 pharmacokinetic profile and parameters - Vss [ Time Frame: 4 months ]
    NI006 apparent volume of distribution at steady state (Vss)

  7. NI006 pharmacokinetic profile and parameters - t½ [ Time Frame: 4 months ]
    Terminal elimination half-life (t½) of NI006 in serum

  8. NI006 pharmacokinetic profile and parameters - AUCtau [ Time Frame: 4 months ]
    Area under the serum concentration-time curve from time zero to the end of the dosing interval after the first dose (AUCtau) of NI006

  9. NI006 pharmacokinetic profile and parameters - RaccCmax [ Time Frame: 4 months ]
    Accumulation ratio for maximum concentration (RaccCmax) of NI006 in serum

  10. NI006 pharmacokinetic profile and parameters - RaccAUC [ Time Frame: 4 months ]
    Accumulation ratio calculated from AUC (RaccAUC) of NI006 in serum

  11. NI006 pharmacokinetic profile and parameters - Ctrough [ Time Frame: 12 months ]
    Minimum observed concentration (Ctrough) of NI006 in serum

  12. NI006 OLE2 pharmacokinetic profile and parameters - Ctrough [ Time Frame: up to 10 months ]
    Minimum observed concentration (Ctrough) of NI006 in serum

  13. NI006 pharmacokinetic profile and parameters - dose-normalized Ctrough [ Time Frame: 12 months ]
    Dose-normalized minimum observed concentration (Ctrough) of NI006 in serum

  14. NI006 OLE2 pharmacokinetic profile and parameters - dose-normalized Ctrough [ Time Frame: up to 10 months ]
    Dose-normalized minimum observed concentration (Ctrough) of NI006 in serum


Other Outcome Measures:
  1. Exploratory - Efficacy of multiple doses of NI006 on 6-Minute Walk Test (6-MWT) [ Time Frame: 4 and 12 months ]
    Changes in 6-MWT

  2. Exploratory - Efficacy of multiple doses of NI006 on patient questionnaire outcome [ Time Frame: 4 and 12 months ]
    Changes in patient questionnaire outcome

  3. Exploratory - Efficacy of multiple doses of NI006 on amyloid load [ Time Frame: 4 and 12 months ]
    Changes in amyloid load assessed by cardiac imaging

  4. Exploratory - Efficacy of multiple doses of NI006 on cardiac biomarkers - NT-proBNP [ Time Frame: 4 and 12 months ]
    Changes in NT-proBNP concentration

  5. Exploratory - Efficacy of multiple doses of NI006 on cardiac biomarkers - Troponin-T [ Time Frame: 4 and 12 months ]
    Changes in Troponin-T concentration

  6. Exploratory - Immunogenicity of NI006 [ Time Frame: 4 and 12 months ]
    Determination of anti-drug antibody response



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Age ≥18 years (and < 85 years only for cohort 7)
  2. Confirmed diagnosis of ATTR-Cardiomyopathy
  3. Known genotype (wild-type or hereditary form)
  4. Chronic Heart Failure with LVEF ≥40%, LVWT ≥14 mm, NT-proBNP ≥ 600 pg/mL, 6-MWT ≥150 meter, no hospitalizations for cardiac disease for at least 30 calendar days prior to screening
  5. Karnofsky Performance Status score ≥60%

Key Exclusion Criteria:

  1. Amyloid light-chain amyloidosis or any other non ATTR amyloidosis
  2. New York Heart Association class IV
  3. NT-proBNP ≥6000 pg/mL (NT-proBNP ≥8500 pg/mL only for cohort 7)
  4. Heart failure not predominantly caused by ATTR-Cardiomyopathy
  5. Any severe uncorrected valve disease
  6. Chronic liver disease with liver function test abnormalities
  7. Respiratory insufficiency requiring oxygen therapy
  8. Renal insufficiency
  9. Active malignancy with exception of: adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, in situ cervical cancer, low risk prostate cancer with Gleason score < 7 and prostate specific antigen < 10 mg/mL, any other cancer from which the subject has been disease-free for ≥ 2 years
  10. Uncontrolled infection, HIV infection, seropositivity for HIV, hepatitis B and C, active hepatitis A
  11. Autoimmune disease requiring immunosuppressive/modulating treatment in the last 2 years
  12. History of organ transplantation or ventricular assist device
  13. Polyneuropathy disability score > IIIA
  14. Suspected or known drug or alcohol abuse, serious psychiatric or any other medical condition, which, in the opinion of the Investigator, makes the subject unsuitable

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04360434


Contacts
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Contact: Christiane Schindeldecker +41 44 755 4612 christiane.schindeldecker@neurimmune.com
Contact: Peter C. Kahr, MD +41 44 755 46 14 peter.kahr@neurimmune.com

Locations
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France
Hôpital Henri Mondor Recruiting
Créteil, France, 94000
CHU de Rennes - Hôpital Pontchaillou Recruiting
Rennes, France, 35033
CHU Toulouse - Hôpital Rangueil Recruiting
Toulouse, France, 31059
Germany
Universitätsklinikum Heidelberg Recruiting
Heidelberg, Germany, 69120
Netherlands
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713
Spain
Hospital Universitario Puerta de Hierro Majadahonda Recruiting
Majadahonda, Spain, 28222
Sponsors and Collaborators
Neurimmune AG
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Responsible Party: Neurimmune AG
ClinicalTrials.gov Identifier: NCT04360434    
Other Study ID Numbers: NI006-101
2019-001932-80 ( EudraCT Number )
First Posted: April 24, 2020    Key Record Dates
Last Update Posted: June 14, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Neurimmune AG:
ATTR
Transthyretin
Amyloidosis
Cardiomyopathy
ATTR-CM
Additional relevant MeSH terms:
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Cardiomyopathies
Amyloidosis
Heart Diseases
Cardiovascular Diseases
Proteostasis Deficiencies
Metabolic Diseases